For convenience, the adaptive immune response to infection in mammals, is often divided into antibody (or humoral) responses and cell-mediated responses. These two arms of the immune response are initiated by different cell types. Thus, antibody immune responses are generated by the antibody producing lymphoid cells referred to as B lymphocytes or B cells, while the adaptive cell-mediated immune response is the direct result of antigen recognition by T lymphocytes or T cells in the context of the major histocompatibility complex (MHC) antigen. The processes involved in these responses and the roles played by these lymphoid cells in infection are now well understood and published works outlining the nature and functioning of these cells are readily available including inter alia: Immunology 5th Edition; I. M. Roitt Ed, Blackwell Scientific Publications, Boston, 1998 and Immunobiology: the Immune System in Health and Disease 4th Edition, C. A. Janeway, P. Travers, M. Walport and J. D. Capra Eds, Elsevier Science/Garland Publishing, New York, 1999; incorporated herein by reference.
T cells perform the role of immunological surveillance by constantly recirculating throughout the body. Most of the recirculation takes place in the movement of T cells from the lymph nodes into the blood stream via the lymphatic ducts and then re-entering the nodes via the nodal post capillary venules. The remaining recirculation takes place when T cells leave the blood stream via capillaries in various tissues of the body, migrate through these tissues into draining lymphatics and thus into the local draining lymph node. If the T cell encounters a specific antigen to which it is capable of responding when recirculating through the tissues it will initiate a cell-mediated immune response. Thus, in the case of an infectious agent the T cell will in most cases respond in a manner that will ultimately result in clearance of the pathogen. In some cases, however, this response may be excessive and result in damage to normal host tissue in the vicinity of the infectious agent. In other cases T cells can initiate an inappropriate immune response. This can happen, for example, when the T cell responds to one of the body's own tissue components. When this happens in a clinically apparent manner, the resulting disorder is termed an autoimmune disease. Descriptions of this process can be found in many scientific and medical publications including The Pathogenesis of Infectious Disease, C. A. Mims Ed; Academic Press, New York, 1982, incorporated herein by reference.
There are many pathological disorders of human beings that are the direct result of autoreactive T lymphocyte mediated inflammation, included among these immunopathological maladies are the autoimmune diseases such as multiple sclerosis (MS), rheumatoid arthritis, acute disseminated encephalomyelitis (ADE) and Type I diabetes (Klein, J. and Horejsi, Vaclav 1997. Autoimmunity and autoimmune diseases, pp 656-657. In: Immunology (Second Edition), Blackwell Science Ltd., Oxford. Psoriasis, although previously believed to be a disorder of keratinocytes, is now known to be a T cell mediated inflammatory disease of the skin; the immunological basis of psoriasis has been reviewed by Bos and De Rie (Bos J. D. and De Rie M. A., (1999). The pathogenesis of psoriasis: immunological facts and speculations. Immunology Today, vol. 20, 40-46; incorporated herein by reference).
It has now been found that compounds of the present invention, which are phosphotetrahydropyrans of Formula (I), may be effective at inhibiting the migration of T lymphocytes from the blood stream into tissues and thus may have utility in the treatment of diseases or conditions mediated by T lymphocyte migration.